Rough skin (dry skin) generally means skin with scaling in a dry state in stratum corneum(S.C.). Such a rough skin occurs due to dissolution of S.C. lipids such as cholesterol, ceramide, fatty acid, etc., and degeneration of corneocytes caused by ultraviolet rays, detergents, etc. or hypoplasia of epidermal permeability barrier due to disintegration of a balance between proliferation and keratinization of keratinocytes or the like. For the puropose of preventing or treating the rough skin, it has been carried out rearches to feed S.C. lipids or its analogues, or to administer a substance controlling proliferation and keratinization of keratinocytes such as epidermal growth factor (EGF), etc.
This S.C. lipids biosynthesized in cells of a spinous layer and granular layer are released to intercellular directly under the S.C., and extended and spread to take a lamellar (lamella) structure. Lamellar granules are constituted by glucosylceramide, cholesterol, ceramide, phospholipids, etc., and substantially no glucosylceramide was contained in S.C. lipids. That is, it can be considered that glucosylceramide in lamellar granules is hydrolyzed by β-glucocerebrosidase and converted into ceramide, and the ceramide has a lamella structure, so that it improves formation of the epidermal peameability barrier as the S.C. lipids, whereby it has a barrier function of preventing from rough skin. For example, in a patient of Type 2 Gaucher's disease in which β-glucocerebrosidase had been genetically and completely defected, morbid rough skin has been observed, and according to histological research on the epidermis, abnormality in lamella structure of S.C. lipids has been admitted. Also, in transgenic mouse in which β-glucocerebrosidase had artificially defected, a correlation between abnormality in a lamella structure of S.C. lipids and rough skin has been admitted. Moreover, when β-glucocerebrosidase is inhibited, rough skin and abnormality in a lamella structure of S.C. lipids have been experimentally observed. From these various facts, it has been suggested that for formation of normal epidermal permeability barrier, it is necessary that the glucosylceramide is hydrolyzed by β-glucocerebrosidase to ceramide. Accordingly, by activating β-glucocerebrosidase, it can be considered that formation of the epidermal permeability barrier can be improved, and as a result, rough skin can be recovered.
Under such a background, as an activator of β-glucocerebrosidase, it has heretofore been known SAP-2 found from guinea pig spleen or Ala or Saposin C found from human Gaucher's disease spleen.
However, these activation factors are proteins and there are great problems to activate β-glucocerebrosidase in epidermis by external application in the points of epidermal absorption and safety. Also, it is extremely difficult to utilize these proteins by isolation for industrial purpose in view of an economical aspect.
On the other hand, as a β-glucocerebrosidase activator other than proteins, β-galactosylceramide has been known.
However, β-galactosylceramide actually applicable is derived from extracts of bovine brain, and to use it externally involves a great problem in the point of safety. Also, it is extremely difficult to synthesize β-galactosylceramide with a large amount and it is expensive, so that these are defects for utilizing it industrially.
Accordingly, an object of the present invention is to provide a β-glucocerebrosidase activator which is easily available, and external skin preparations and a method of activating β-glucocerebrosidase, in which improvement in formation of epidermal permeability barrier is expected by activating β-glucocerebrosidase so that an improved effect in rough skin is also expected.